The mechanism of leukocyte activation by chemotactic factors has been studied using electrophysiology, fluorescent probe, surface charge and ultrastructural techniques in leukocytes from normal subjects and patients with abnormal phagocytes. A severe defect in elicited membrane potential charges in neutrophils from patients with chronic granulomatous disease has been seen. Studies assessing the mechanism of modulating leukocyte locomotion indicate that limited secretion of specific granules, which accompanies chemotaxis, is associated with increased cell adhesiveness and increased availability of chemo-attractant receptors. Limited secretion may be required for neutrophil margination in vivo. Studies of the two populations of neutrophils we had identified previously indicate that during the neutropenia that follows in vivo endotoxin or hemodialysis, a subpopulation of neutrophils with poorly demonstrable Fc receptors is the predominant neutrophil left in the circulation. Clinical studies assessing the effect of pharmacologic agents on the neutrophil subpopulations in normal subjects, patients with recurrent infection and host defense are underway.